Nerve regeneration is a complex biological phenomenon. Mature neurons do not replicate; in other words, they do not undergo cell division. Once the nervous system is impaired, it is very difficult to recover, and failures in other parts of the body may occur. In the peripheral nervous system (PNS), nerves can regenerate on their own if injuries are small. Even though regeneration occurs after injury to the adult PNS, it does not always result in functional recovery. This is primarily due to misdirection of regenerating axons toward an inappropriate target. When the nerve is separated by a gap greater than 1 cm in length, the lack of specific guidance can lead axons growing backwards into the proximal nerve stump, entering an inappropriate endoneurium, or forming neuromas. In all these conditions, injured axons can take several months to regenerate. To increase the prospects of axonal regeneration and functional recovery, numerous strategies have been used. These have included implantation of autografts, allografts, xenografts, and Schwann cell (SC)-filled tubes. A number of problems may arise from autologous grafting including: donor site morbidity, denervation distal to the donor site, neuroma formation and the fact that there are a limited number of suitable sites available for nerve harvesting. These disadvantages have led to the development of artificial nerve grafts.
Researches have focused on the creation of tubes, or nerve guides, to bridge the gap between transected nerves in both the CNS (central nervous system) and PNS. Of the numerous entubulation studies reported to date, some of the best results have been achieved in the PNS (S. E. Mackinnon and A. L. Dellon, Plastic Reconstructive Surg, 85: 419-24 (1990); M. F. Meek et al., Microsurgery, 19: 247-53 (1999); S. T. Li et al., Clin Mater, 9: 195-200 (1992)). In addition to the biodegradability and biocompatibility issues, the influence of a variety of physical parameters of the conduits, such as conduit diameter and length, lumenal surface microgeometry, and wall porosity and permeability have been established.
Introduction of cultured SCs into the lumen of a synthetic nerve graft enhances peripheral nerve regeneration (V. Guenard et al., J Neurosci, 12: 3310-20 (1992)). For SCs to survive in the graft, attachment is mandatory, since attachment is a prerequisite for survival and proliferation of SCs. Laminin, the extracellular matrix protein, is a permissive protein for SCs adhesion used in neural regeneration. Laminin can interact with the integrins on the SC surface and support SC attachment and proliferation. Madison et al. disclosed the use of a bioresorbable nerve guide filled with a laminin-containing gel to hasten axonal regeneration in mice (Madison et al., Experimental Neurology, 88: 767-772 (1985)). However, the manufacture of tubes filled with such promoting agents is a relatively expensive and tedious process. Rangappa et al. disclosed the use of a nerve guide filled with aligned laminin-coated poly(l-lactide) filaments to induce robust neurite growth and provide directional orientation (N. Rangappa et al., J Biomed Mater Res, 51: 625-34 (2000)). However, the arrangement of the filaments within the guidance channels is irregular and difficult to reproduce. U.S. Pat. Nos. 4,963,146 and 5,019,087 disclosed hollow conduits for promoting the in vivo regeneration of a severed mammalian nerve having walls comprised of Type I collagen and laminin-containing material, as well as methods for preparing such conduits. The methods comprise the steps of forming a dispersion containing Type I collagen and a laminin-containing material; adding a precipitating agent to the dispersion; and contacting the precipitate with a spinning mandrel to form a tubular collagen membrane.
Studies have suggested that the interactions between the biological environment and artificial materials are most likely dominated by the materials' “surface properties”. Hence, surface modification of existing biomaterials with an aim towards improving a material's biocompatibility has been a major focus of biomaterials research in recent years. Several synthetic approaches, such as grafting long alkyl chains or bioactive molecules, have been attempted in different laboratories. These synthetic methods often lead to alterations of the original material's physical properties. In contrast, the plasma surface modification process has been shown to be able to modify the surface properties of a biomaterial without affecting its bulk physical properties. In addition, a wide range of chemicals, including those which are not polymerizable by conventional synthetic methods, can be used to incorporate specific functional groups into the substrate.
Gas plasma treatment is extensively used for chemical modification of poly(lactic acid) (PLA) or poly(lactic-co-glycolic acid) (PLGA). Nonpolymerizing gas plasma can create reactive sites such as peroxide and sulfonic acid groups on the surface of polymers. Plasma processes have been used to increase the hydrophilicity of PLA and to improve its cell adhesion (J. Yang et al., Polym Adv Technol, 13: 220-6 (2002)). As an alternative method, combining plasma treatment and collagen anchorage could also improve the cell affinity of PLA significantly (J. Yang et al., Biomaterials, 23: 2607-14 (2002)). Such results indicate that the surface composition and the functional groups on the surface of a polymer after plasma treatment had a great effect on the cell affinity of said polymer.
Although improved results in nerve regeneration have been obtained through the use of nerve guides/conduits comprising cell-adhesive molecules such as laminin, there is still much room for further improvement. Moreover, it would still be desirable to provide a means by which an even greater number of myelinated axons is regenerated, a faster rate of nerve growth is achieved, and longer nerve gaps are spanned. A need still exists to fulfill such a need and still reduce or eliminate problems that have been encountered with prior art nerve repair attempts such as revascularization, excessive fibrosis, reorientation of nerve fibers, and the final poor return of function of the end organs.